PD-1/PD-L1 signal pathway participates in HCV F protein-induced T cell dysfunction in chronic HCV infection

Abstract

Programmed cell death-1/programmed cell death-1 ligand 1 (PD-1/PD-L1) inhibitory signal pathway has been verified to be involved in the establishment of persistent viral infections. Blockade of PD-1/PD-L1 engagement to reinvigorate T cell activity is supposed to be a potential therapeutic scheme. Studies have verified the participation of PD-1/PD-L1 in hepatitis C virus (HCV) core protein-regulated immune response. To determine the roles of PD-1/PD-L1 signal pathway in HCV F protein-induced immunoreaction in chronic HCV infection, variations in T cells were examined. The results showed that PD-1 expression on CD8(+) and CD4(+) T cells was increased with HCV F stimulation in both chronic HCV patients and healthy controls, and could be reduced partly by PD-1/PD-L1 blocking. Additionally, by PD-1/PD-L1 blocking, HCV F-induced inhibition of T cell proliferation and promotion of cellular apoptosis were partly or even totally recovered. Furthermore, levels of both Th1 and Th2 cytokines were elevated in the presence of anti-PD-L1 antibody. All these results indicated that PD-1/PD-L1 signal pathway also participates in HCV F protein-induced immunoregulation. PD-1/PD-L1 blocking plays important roles in the restoration of effective functionality of the impaired T cells in chronic HCV patients.

Immune Checkpoints in Viral Infections

“…The secretion of Th1 cytokines increases in the acute phase of hepatitis virus infection, then decreases rapidly with disease progression because of viral-specific T-cell dysfunction [163][164][165][166]. In contrast, Th2 cytokines, such as IL-4 and IL-10, are less affected, while increases in TGF-β and IL-35 levels can downregulate Th1 responses and decrease T-cell function [147,[167][168][169]. Cytokine secretion varies among subsets of Th2 and Treg cells.…”

Human CD8+CD28− T Suppressor Cells Expanded by IL-15 In Vitro Suppress in an Allospecific and Programmed Cell Death Protein 1-Dependent Manner

“…Moreover, suppression by CD8 + CD28 − Ts cells was partially abolished when anti-PD-1 or anti-PD-L1 was added into the suppressing assay (Figure 8 ). Co-inhibitory signals PD-1:PD-L1 pathway had been found to play a key role in T cell exhaustion in chronic viral infection diseases ( 38 ), autoimmunity ( 25 , 39 ), antitumor immunity ( 40 ), and recently in allograft tolerance in animal transplant model ( 41 ). Our results indicate that PD-1:PD-L1 pathway plays a role in the suppression mechanisms for CD8 + CD28 − Ts cells although it does not account for all.…”

Viral Manipulation of Host Inhibitory Receptor Signaling for Immune Evasion

“…correlate to the control of both HCV and HIV-1 replication, while blocking PD-1 enhanced T cell proliferation [44,45]. T cell exhaustion is not unique to chronic infections but could also rapidly develop in acute viral respiratory infections with human metapneumovirus (HMPV) [46] or respiratory syncytial virus (RSV) [47].…”